Unexpected coccidioidomycosis presenting as lung nodules with presumptive diagnosis of malignancy

Key clinical message Coccidioidomycosis can present as fluorodeoxyglucose (FDG) avid lung nodules which may be mistaken as relapse in patients with a history of malignancy. Detailed clinical history, relevant laboratory testing, and/or tissue biopsy with histologic evaluation are necessary for correct diagnosis.

years later, she was found to have a liver lesion which was considered clinically and radiographically consistent with hepatocellular carcinoma based on the hepatic multiphase computed tomography (CT) findings and elevated serum alpha-fetoprotein (AFP) level in the setting of cirrhosis.She was treated with transarterial chemoembolization (TACE).After 1 year, she developed a second relapse of her lymphoma in the liver and was treated with 13 cycles of R-GemOx (rituximab, gemcitabine, and oxaliplatin) with a complete metabolic response.At the current presentation, to monitor her malignant diseases, a surveillance whole-body Positron emission tomographycomputed tomography (PET/CT) scan was performed and showed a new, fluorodeoxyglucose (FDG) avid left lower lobe pulmonary nodule measuring 2.5 cm in diameter with an SUV max of 8.6 (Figure 1), concerning for malignancy.Her complete blood count (CBC) with automatic differential 3 days before the PET/CT showed mild normocytic anemia (Hgb 11.1 g/dL, MCV 87.5 fL), mild leukopenia (WBC 4.2 K/cumm, with 75.3% neutrophils, 15.5% lymphocytes, 7.9% monocytes, 1.0% eosinophils, and 0.3% basophils), and moderate thrombocytopenia (56 K/cumm).A follow-up CT of her thorax 2 months after the PET-CT demonstrated that the lung nodule had decreased in diameter to 1.5 cm, but with multiple additional new bilateral lung micronodules ranging from 1 to 6 mm in diameter (Figure 2).Although the decrease in nodule size raised the possibility of infection, given the multiple new bilateral pulmonary micronodules and the high clinical suspicion for malignancy, a CT-guided core biopsy of the largest lung nodule was performed, which showed both necrotizing and non-necrotizing granulomas (Figure 3).Many Coccidioides spherules were seen in the necrotic centers of the granulomas, ranging in size from 20 to 200 microns in diameter, and containing endospores (Figure 4).The Grocott-Gömöri's methenamine silver (GMS) stain highlighted Coccidioides spherules (Figure 5).The acid-fast bacteria (AFB) stain was negative for acid-fast bacilli.By immunohistochemistry, many CD3-positive small T-cells were seen, with virtually no B-cells by CD20 and PAX-5 stains.The findings were consistent with coccidioidomycosis.There was no evidence of lymphoma or carcinoma.Her serum Coccidioides Serology Panel (Quest Diagnostics Nichols Institute, San Juan Capistrano, CA) showed an antibody titer of 1:2 (Complement Fixation, reference range: < 1:2), but with negative antibodies to Coccidioides F antigen (IgG Immunodiffusion) and TP antigens (IgM Immunodiffusion).Antibodies to Coccidioides were not detected in her cerebrospinal fluid (CSF) by either complement fixation or immunodiffusion.She also denied joint swelling or pain.The patient underwent 8 months of fluconazole treatment.A follow-up PET/CT scan after 6 months of treatment showed decreased FDG uptake of the left lower lobe pulmonary nodule (no change in size, still 2.5 cm in diameter) with an SUV max of 2.2, and no evidence of hypermetabolic disease recurrence (Figure 6).As of 10 months postcompletion of antifungal therapy, her bilateral lung lesions remain stable by serial CT scans and magnetic resonance imaging (MRI), without signs of recurrence of malignancy.The size of the left lower lobe pulmonary nodule remained at 2.2-2.3 cm in diameter by CT and at 2.4 cm in diameter by MRI.

| DISCUSSION
An FDG PET scan is commonly used to detect metabolically active malignant lesions and may be used to more accurately stage malignant diseases and to monitor the therapy response of malignant diseases.However, although it is especially helpful in detecting metastatic malignancy, FDG-positive lesions can also be seen in nonmalignant conditions including infections such as coccidioidomycosis, 4 inflammations, autoimmune disorders, sarcoidosis, and benign tumors. 5If these conditions are not identified clinically and/or by tissue biopsies, misdiagnosis can lead to inappropriate therapies.Our case describes an FDG-positive lung nodule in a patient with a history of both diffuse large B-cell lymphoma and hepatocellular carcinoma.Given the malignant history and the lack of symptoms and laboratory evidence of lung infection, relapsed malignancy was highly suspected.This case emphasizes the importance

F I G U R E 6 A coronal maximal intensity projection (MIP) fluorodeoxyglucose positron emission tomography (FDG PET)
following fluconazole therapy shows that the FDG avidity of the pulmonary nodule in the left lower lobe significantly decreased to background physiologic levels.
tissue biopsy and histologic evaluation in patients diagnosed with FDG avid lesions.
Coccidioidomycosis, also known as cocci or Valley fever, is a disease caused by the dimorphic fungus Coccidioides immitis or Coccidioides posadasii which exists either as mycelia in the soil or as spherules in the lung and other tissues.Infections are established mainly through inhalation of aerosolized arthrospores into the lung or less likely through direct skin contact 6 or transplanted organs. 7Hematogenous extrapulmonary systemic dissemination occurs in 1% of infections. 8Coccidioidomycosis is endemic to the southwestern United States, northern Mexico, and South America. 6,8Upon further inquiry after the histologic diagnosis was made, our patient admitted that she had traveled to Arizona a few months before the finding of her pulmonary nodule.The clinical manifestations of coccidioidomycosis vary.Symptoms may include fever, cough, shortness of breath, chest pain, headache, weight loss, skin rash, and migratory arthralgias. 9owever, most infections are asymptomatic, as seen in the present case.In disseminated coccidioidomycosis, central nervous system (CNS) involvement is often seen, which can be fatal.Thus, it is important to rule out CNS involvement by CSF study.
Both asymptomatic and symptomatic pulmonary coccidioidomycosis can result in radiographically visible lung nodules 7 and it is difficult to differentiate lung nodules due to coccidioidomycosis from those due to malignancy radiographically.Cavitary nodules, satellite nodules, and chronic lung disease, in patients from endemic regions may support coccidioidomycosis rather than primary lung cancer. 10Definitive diagnosis of coccidioidomycosis relies on careful clinical evaluation and laboratory diagnostic testing.Young age (< 55 years old), absence of past lung diseases, a job in the farming or construction sector, and/ or traveling in the endemic regions will raise the possibility of coccidioidomycosis. 11Microbiological culture, histopathological evaluation, or serological testing should be used to confirm the diagnosis. 12Serological assays such as enzyme immunoassay (EIA), immunodiffusion, and complement fixation may be less reliable 3,13,14 and often a biopsy is required to establish the diagnoses via histopathology, culture, and possibly PCR.Histologically, granulomas are seen in all cases, with or without necrosis. 15The presence of endospore-containing spherules is diagnostic of coccidioidomycosis.In our patient, the biopsy of her pulmonary nodule showed many necrotizing and nonnecrotizing granulomas; numerous spherules containing endospores were seen in the necrotic centers of the granulomas, supporting the diagnosis of coccidioidomycosis.
It is challenging to differentiate between Coccidioides immitis and Coccidioides posadasii because they have identical morphology and similar phenotypes.Fortunately, this differentiation is unnecessary as the two species seem to have almost identical clinical presentations and antifungal susceptibility profiles. 16symptomatic pulmonary nodules attributed to coccidioidomycosis in an immunocompetent patient do not require treatment. 14However, azole antifungals may be used in other patients depending on patient risk factors, serologic studies, and characteristics of the lesions. 14ntravenous amphotericin B should be reserved only for those with severe disease. 14,17Current therapies do not eradicate Coccidioides species from the lesions of chronic coccidioidal pneumonia and symptoms may recur. 14hus, regular follow-up is an important component in the management of coccidioidomycosis, to confirm that the infection remains uncomplicated. 14As long as repeated radiographic imaging demonstrates the lesions are stable over time and the disease shows a benign clinical course, further intervention is unnecessary.Whether or not antifungal therapy is administered, the infection will eventually resolve in uncomplicated cases.
In conclusion, although lung nodules, especially FDG avid ones, in patients with a history of malignancy warrant a high suspicion for malignant recurrence, clinicians should still maintain vigilance for excluding other potentially treatable infectious etiologies, even in patients without symptoms of infections because infections such as coccidioidomycosis tend to manifest without symptoms.Detailed clinical history, relevant laboratory testing, and/ or tissue biopsy with histologic evaluation are necessary for accurate diagnosis.

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I G U R E 1 A coronal maximal intensity projection (MIP) fluorodeoxyglucose positron emission tomography (FDG PET) shows a 2.5 cm FDG avid pulmonary nodule in the left lower lobe.F I G U R E 2 An axial noncontrast computed tomography (CT) slice at the lower chest in the lung window shows a new 6 mm juxta pleural nodule along the medial margin of the right lower lobe.F I G U R E 3 Photomicrograph of the computed tomography (CT)-guided core biopsy of the lung nodule.The lung tissue is largely replaced by granulomas with or without central necrosis.(H&E stain, original magnification, × 40).

F I G U R E 4
Photomicrograph of the computed tomography (CT)-guided core biopsy of the lung nodule.There are numerous Coccidioides spherules containing endospores in the necrotic centers of the granulomas (H&E stain, original magnification, × 400).F I G U R E 5 Photomicrograph of the computed tomography (CT)-guided core biopsy of the lung nodule.The Grocott-Gömöri's methenamine silver stain highlights the Coccidioides spherules (original magnification, × 400).